Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function

Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2167-72. doi: 10.1152/ajpheart.00935.2001.


The present study was designed to investigate the interaction between 5-methyltetrahydrofolate and tetrahydrobiopterin in modulating endothelial function. Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide- versus superoxide-producing enzyme. The structure of 5-methyltetrahydrofolate is similar to tetrahydrobiopterin and both agents have been shown to improve endothelium-dependent vasodilatation. We hypothesized that 5-methyltetrahydrofolate interacts with nitric oxide synthase in a fashion analogous, yet independent, of tetrahydrobiopterin to improve endothelial function. We demonstrate that 5-methyltetrahydrofolate binds the active site of nitric oxide synthase and mimics the orientation of tetrahydrobiopterin. Furthermore, 5-methyltetrahydrofolate attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis) and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function. 5-Methyltetrahydrofolate may represent an important strategy for intervention aimed at improving tetrahydrobiopterin bioavailability.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Aorta
  • Binding Sites
  • Biopterin / analogs & derivatives*
  • Biopterin / deficiency
  • Biopterin / metabolism
  • Biopterin / pharmacology*
  • Cattle
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology*
  • Fluorescent Dyes
  • Free Radicals
  • Immunohistochemistry
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Pteridines / pharmacology
  • Pterins*
  • Reactive Oxygen Species / metabolism
  • Rhodamines
  • Superoxides / metabolism
  • Tetrahydrofolates / metabolism
  • Tetrahydrofolates / pharmacology*
  • Vasodilation / drug effects


  • Fluorescent Dyes
  • Free Radicals
  • Pteridines
  • Pterins
  • Reactive Oxygen Species
  • Rhodamines
  • Tetrahydrofolates
  • dihydrorhodamine 123
  • Superoxides
  • Biopterin
  • Nitric Oxide
  • sepiapterin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • sapropterin
  • Acetylcholine
  • 5-methyltetrahydrofolate